1gqr

ACETYLCHOLINESTERASE (E.C. 3.1.1.7) COMPLEXED WITH RIVASTIGMINE
(see also AChE inhibitors and substrates (Part III)



Rivastigmine (Exelon) is a carbamate inhibitor of AChE, and it is currenly used in therapy of Alzheimer's disease. Rivastigmine (colored yellow) interacts with TcAChE (colored lime) at the active-site gorge (1gqr). The carbamyl moiety of rivastigmine is covalently bound to the active-site S200 Oγ. The second part of rivastigmine (the leaving group), NAP ((−)-S-3-[1-(dimethylamino)ethyl]phenol) is also held in the active-site gorge, but it is separated from the carbamyl moiety, hence, carbamylation took place. The crystal structure of TcAChE/NAP (colored magenta) is known (1gqs). The TcAChE active-site residues which are interacting with NAP are colored violet. NAP is located in a similar region of TcAChE active site, but with different orientation than that of the NAP part (colored yellow) in the TcAChE/rivastigmine complex. Only H440 and F330 significantly change their side-chain conformations. Overlap of the TcAChE active sites in 4 different structures (TcAChE /rivastigmine (1gqr, yellow), TcAChE /NAP (1gqs), native TcAChE (2ace), and TcAChE/VX (1vxr, TcAChE colored white and VX black)) reveals that the conformation of H440 in the TcAChE/NAP structure is very similar its conformation in the native TcAChE (2ace), but the distance between H440 Nδ and E327 Oε is significantly longer in the TcAChE/rivastigmine and the TcAChE/VX complexes. This structural change disrupts the catalytic triad consisting of S200, E327, H440. This could explain the very slow kinetics of AChE reactivation after its inhibition by rivastigmine.

About this Structure
1GQR is a Single protein structure of sequence from Torpedo californica. Full crystallographic information is available from OCA.

Reference
Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine., Bar-On P, Millard CB, Harel M, Dvir H, Enz A, Sussman JL, Silman I, Biochemistry. 2002 Mar 19;41(11):3555-64. PMID:11888271

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